In 2004, the laboratories of Pettit and coworkers first published the isolation, structural elucidation, and biological activity of (+)-irciniastatin A and (−)-irciniastatin B. Pettit, G. R.; Xu, J. P.; Chapuis, J. C.; Pettit, R. K.; Tackett, L. P.; Doubek, D. L.; Hooper, J. N. A.; Schmidt, J. M. Journal of Medicinal Chemistry 2004, 47, 1149-1152. Pettit and coworkers first collected samples containing irciniastatins A and B from the Indo-Pacific marine sponge Ircinia ramosa near Samporna, Borneo in 1991. The dichloromethane-methanol extracts exhibited strong activity (GI50=10−2 μg/mL) against the P388 murine lymphocytic leukemia cancer cell line. Unfortunately, recollection on a larger scale to allow for isolation of the individual constituents was not permitted (political obstacles) and so the extracts were preserved for later use. As isolation techniques advanced over the past decade, irciniastatins A and B were isolated as an individual constituent (34.7 mg and 2.2 mg, respectively) from the initial dichloromethane-methanol extracts.
After isolating irciniastatins A and B, Pettit and coworkers tested the compound against cancer cell lines, including the P388 murine lymphocytic leukemia cell line and human umbilical vein endothelial cells (HUVEC) (Table 1.1). Id.
TABLE 1.1Growth Inhibition of Cancer Cell Lines (GI50, μg/mL) byIrciniastatins A and BCancer Cell LineIrciniastatin AIrciniastatin BpancreasBXPC-30.00380.00073breastMCF-70.00320.0005CNSSF-2680.00340.00066lungNCI-H460<0.00010.0012colonKM20L20.00270.0021prostateDU-1450.00240.0016leukemiaP3880.004130.006normal endothelialHUVEC<0.0005ND
Additionally, (+)-irciniastatin A was evaluated against the panel of 60 human cancer cell lines within the NCI Developmental Therapeutics in Vitro Screening Program (Table 1.2).
TABLE 1.2Differential Sensitivities (LC50) of Several NCI 60 CellLines to (+)-Irciniastatin ACell LineLC50 (M)Cell LineLC50 (M)leukemiamelanomaCCRF-CEM>2.5 × 10−5LOX IMVI>2.5 × 10−5HL-60(TB)>2.5 × 10−5MALME-3M<2.5 × 10−9K-562>2.5 × 10−5SK-MEL-2>2.5 × 10−5MOLT-4>2.5 × 10−5SK-MEL-5<2.5 × 10−9RPMI-8226>2.5 × 10−5UACC-257>2.5 × 10−5SR>2.5 × 10−5UACC-62<2.5 × 10−9breast cancercolon cancerMCF7>2.5 × 10−5HCC-2998 3.6 × 10−7HS 578T>2.5 × 10−5HCT-116<2.5 × 10−9MDA-MB-435<2.5 × 10−9HT29>2.5 × 10−5NCI/ADR-RES 1.9 × 10−5SW-620>2.5 × 10−5T-47D1.36 × 10−5
(+)-Irciniastatin A exhibits activities in the low nanomolar range for the MDA-MB-35 breast cancer, SK-MEL-28 and UACC-62 melanoma, and the HCT-116 colon cancer cell lines with an activity differential of greater than 10,000-fold as compared to other cell lines within their respective subsets. Burres, N. S.; Clement, J. J. Cancer Res. 1989, 49, 2935-2940; Kobayashi, J. I.; Itagaki, F.; Shigemori, H.; Sasaki, T. Journal of Natural Products 1993, 56, 976-981; West, L. M.; Northcote, P. T.; Hood, K. A.; Miller, J. H.; Page, M. J. Journal of Natural Products 2000, 63, 707-709; Hood, K. A.; West, L. M.; Northcote, P. T.; Berridge, M. V.; Miller, J. H. Apoptosis 2001, 6, 207-219; Paul, G. K.; Gunasekera, S. P.; Longley, R. E.; Pomponi, S. A. Journal of Natural Products 2002, 65, 59-61.
(+)-Irciniastatin A was also evaluated in the NCI Developmental Therapeutics Program hollow fiber assay using several solid tumor cell lines resulting in an overall score of 34 (compounds considered active score 20 or higher), based on scores of 28 against intraperitoneal fibers and 6 against subcutaneous fibers. Robinson, S. J.; Tenney, K.; Yee, D. F.; Martinez, L.; Media, J. E.; Valeriote, F. A.; vanSoest, R. W. M.; Crews, P. Journal of Natural Products 2007, 70, 1002-1009.
Analogues of irciniastatin have been only sparingly investigated. For example, De Brander prepared analogues to investigate the bioactivity where the psymberate (C-1 to C-8) and didhydroisocoumarin side chains were altered.
Various compounds prepared and evaluated by De Brander et al.

Varying biological activity was observed. Wu, C. Y.; Feng, Y.; Cardenas, E. R.; Williams, N.; Floreancig, P. E.; De Brabander, J. K.; Roth, M. G. J. Am. Chem. Soc. 2012, 134, 18998-19003.
TABLE 1.3Cytotoxicitya and Translation Inhibition of Analogues of Irciniastatintranslation inhibition (EC50 nM)acytotoxicity (IC50 nM)cell-based assaycompoundHelacSK-MEL-Sdin vitro assayHelaSK-MEL-Scycloheximide2292 ± 15253126 ± 764  3150 ± 23523325 ± 434 2670  1a0.64 ± 0.140.27 ± 0.0428 ± 7 22 ± 1.433 ± 10 1b0.54 ± 0.010.35 ± 0.07342 ± 215.8 ± 1.74.2 ± 5.2 1c2.34 ± 0.531.58 ± 0.42320 ± 479.6 ± 8.99.3 ± 8.582.52 ± 1.393.79 ± 0.04238 ± 4459 ± 32 643613.6 ± 267.0352.0 ± 12.1 346 ± 644950 ± 48704954>1000762.8 ± 70.0  318 ± 1822200 ± 14108435>1000>1000 641 ± 2621650 ± 10605786>1000>1000>10 000>10 000>10 000   7>1000>1000>10 000>10 000>10 000   aA CellTiter-Glo luminescent assay, which measures cellular ATP concentrations, was used to measure cell viability with and without compound treatment. IC50 values were calculated by fitting the luminescence data to an equation representing the dose-response of inhibiting luminescence.bData are means ± standard deviation from at least two independent experiments conducted as triplicate.cR2 values range from 0.931 to 0.994.dR2 values range from 0.865 to 0.997.eR2 ranges from 0.90 to 0.995.
Huang et al. also prepared analogues by altering the psymberate side chain. Additionally, the C11-deoxyirciniastatin demonstrated 3 to 10 times the potency of irciniastatin against various cancer types. Huang, X.; Shao, N.; Huryk, R.; Palani, A.; Aslanian, R.; Seidel-Dugan, C. Org. Lett. 2009, 11, 867-870.
TABLE 1.4Anticancer Activity of C11-Deoxyirciniastatin and its Epimersa29 29a 29b 29c 2929a29b29ccellhuman(IC50 nM)(IC50 nM)(IC50 nM)(IC50 nM)linetissue type0.265 ± 0.008n.d.n.d.8.7 ± 0.18ACHNkidney0.149 ± 0.005n.d.n.d.5.9 ± 0.18DU145prostate0.034 ± 0.004n.d.n.d.1.6 ± 0.27H226lung0.055 ± 0.002177 ± 646 ± 73.0 ± 0.12HOP62lung0.142 ± 0.007n.d.n.d.5.3 ± 0.15MB231breast0.076 ± 0.004n.d.n.d.3.9 ± 0.48MKN45gastric0.073 ± 0.006n.d.n.d.2.9 ± 0.21 PC3prostate0.160 ± 0.015n.d.n.d.6.1 ± 0.22SW620colon0.066 ± 0.004n.d.n.d.3.8 ± 0.10NHDFnormalaThe CellTiter-Glo Luminescent Cell Viability Assay (Promega, Technical bulletin 288) was employed in this study. IC50 data are the mean value of three experiments with statistical significance calculated.
However, the full structure-activity relationship is not fully developed and there is a need for more irciniastatin analogues.